This invention relates to certain novel benzo[c]-quinolines and more particularly to certain 9-amino-1-hydroxyoctahydrobenzo[c]quinolines and derivatives thereof, especially certain amide derivatives of the 9-amino group, and pharmaceutically acceptable acid addition salts thereof useful as CNS agents, especially as analgesics and antiemetic agents for use in mammals, including man; methods for their use and pharmaceutical compositions containing them.
An acceptable alternative nomenclature for the herein described compounds of formula (I) is based upon replacement of the root "benzo[c]quinoline" with "phenanthridine." Thus, dl-trans-5,6,6a,7,8,9,10,10a-octahydro-1-acetoxy-9beta-acetamido-6-beta-me thyl-3-(5-phenyl-2-pentyloxy)benzo[c]quinoline becomes dl-trans-5,6,6a,7,8,9,10,10a-octahydro-1-acetoxy-9beta-acetamido-6beta-met hyl-3-(5-phenyl-2-pentyloxy)phenanthridine.
Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesics such as d-propoxyphene, codeine, and morphine, possess addictive liability. The need for improved and potent analgesics is, therefore, evident.
Belgian Patent No. 854,655, granted Nov. 16, 1977, describes compounds of the formulae ##STR5## and the corresponding 9-hydroxy compounds wherein R.sub.1, R.sub.4, R.sub.5, R.sub.6, Z and W are as defined herein. The ketones of formula (II) and the corresponding 9-hydroxy compounds are stated to be useful as CNS agents, especially as analgesics and tranquilizers, as hypotensives, diuretics and as agents for treatment of glaucoma. Copending U.S. application Ser. No. 52,324, filed June 26, 1979, discloses compounds of formula (II) and corresponding 1,9 dihydroxy-octahydrobenzo[c]quinolines as antiemetic agents.
The analgesic properties of 9-nor-9beta-hydroxyhexahydrocannabinol and of other cannabinoid structures, such as delta-8-tetrahydrocannabinol (delta-8-THC) and its primary metabolite, 11-hydroxy-delta-8-THC, have been reported by Wilson and May, Absts. Papers, Am. Chem. Soc., 168 Meet., MEDI 11 (1974), J. Med. Chem. 17, 475-476 (1974), and J. Med. Chem., 18, 700-703 (1975).
A series of structurally related dibenzo[b,d]pyrans, having at the 9-position substituents such as alkyl, hydroxy and oxo, are disclosed in U.S. Pat. Nos. 3,507,885; 3,636,058; 3,649,650; 3,856,821; 3,928,598; 3,944,673, 3,953,603 and 4,143,139. Particularly of interest is dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hex ahydro-9H-dibenzo[b,d]pyran-9-one, an antiemetic, antianxiety agent with analgesic properties in animals, now generally referred to as nabilone.
U.S. Pat. No. 4,152,450 discloses certain 3-alkyl-1-hydroxytetrahydro and hexahydrodibenzo[b,d]pyrans, having an amino or amido group at the 9-position, which are useful as analgesics, antidepressants, antianxiety agents and hypotensive agents.
U.S. Pat. No. 3,878,219 discloses 5H-[1]benzopyrano[3,4-d]pyridines useful as analgesics and U.S. Pat. No. 3,888,946 discloses a corresponding class of compounds in which the C-ring is five membered rather than six membered.
Bergel et al., J. Chem. Soc., 286 (1943) investigated the replacement of the pentyl group at the 3-position of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol by alkoxy groups of four to eight carbon atoms and found that these compounds had little or no hashish activity at 10 to 20 mg/kg.
In a more recent study, Loev et al., J. Med. Chem., 16, 1200-1206 (1973) report a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-o ls in which the 3-substituent is --OCH(CH.sub.3)C.sub.5 H.sub.11 ; --CH.sub.2 CH(CH.sub.3)C.sub.5 H.sub.11 ; or --CH(CH.sub.3)C.sub.5 H.sub.11. The ether side chain containing compound was 50% less active in central nervous system activity than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring, rather than through an intervening oxygen atom; and 5 times as active as the compound in which oxygen is replaced by methylene.
Hoops et al., J. Org. Chem., 33, 2995-2996 (1968) describe the preparation of the 5-aza analog of delta-6a(10a)-tetrahydrocannabinol referred to therein as 7,8,9,10-tetrahydro-1-hydroxy-5,6,6,9-tetramethyl-3-n-pentylphenanthridine , but report no utility for the compound. Beil, in "Psychomimetic Drugs", edited by Efron, Raven Press, New York, 1970, page 336, reports the compound was "completely inert in animal pharmacology."
Hardman et al., Proc. West. Pharmacol. Soc., 14, 14-20 (1971) reports some pharmacological activity for 7,8,9,10-tetrahydro-1-hydroxy-6,6,9-trimethyl-3-n-pentyl phenanthridine, a 5-aza-delta-6a(10)a-tetrahydrocannabinol.
Mechoulam and Edery in "Marijuana", edited by Mechoulam, Academic Press, New York, 1973, page 127, observe that major structural changes in the tetrahydrocannabinol molecule seem to result in steep reductions in analgesic activity.
Paton, in Annual Review of Pharmacology, 15, 192 (1975) presents generalizations on structure-action relationships among cannabinoids. The presence of the gem dimethyl group in the pyran ring is critical for cannabinoid activity and substitution of N for O in the pyran ring removes activity.
U.S. Pat. No. 4,087,545 discloses the antiemetic and antinausea properties of 1-hydroxy-3-alkyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones.
Sallan et al., N. E. J. Med. 293, 795 (1975) reported oral delta-9-tetrahydrocannabinol has antiemetic properties in patients receiving cancer chemotherapy.
Delta-9-tetrahydrocannibinol is reported by Shannon et al. (Life Sciences 23, 49-54, 1978) to lack antiemetic effects in apomorphine-induced emesis in the dog. Borison et al., N. England J. of Med. 298, 1480 (1978) report the use of unanesthetized cats as an animal model for determining the antiemetic effect of compounds especially in connection with emesis induced by cancer chemotherapy drugs. They found that pretreatment of unanesthetized cats with 1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro- 9H-dibenzo[b,d]pyran-9(8H)-one (nabilone) affords pronounced protection against vomiting per se after injection of antineoplastic drugs.